MyD88, an Adapter Protein Involved in Interleukin-1 Signaling

doi:10.1074/jbc.273.20.12203

MyD88, an Adapter Protein Involved in Interleukin-1 Signaling*

From the ^‡Institute of Biochemistry,^¶Ludwig Institute of Cancer Research, Lausanne Branch, University of Lausanne, Switzerland, ^**Swiss Institute for Experimental Cancer Research (ISREC), Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland, ^‖Center of Tumor Biology, Breisacher Strasse 117, 79106 Freiburg, Germany, and ^‡Department of Dermatology, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland

Abstract

MyD88 has a modular organization, an N-terminal death domain (DD) related to the cytoplasmic signaling domains found in many members of the tumor necrosis factor receptor (TNF-R) superfamily, and a C-terminal Toll domain similar to that found in the expanding family of Toll/interleukin-1-like receptors (IL-1R). This dual domain structure, together with the following observations, supports a role for MyD88 as an adapter in IL-1 signal transduction; MyD88 forms homodimers in vivo through DD-DD and Toll-Toll interactions. Overexpression of MyD88 induces activation of the c-Jun N-terminal kinase (JNK) and the transcription factor NF-κB through its DD. A point mutation in MyD88, MyD88-lpr (F56N), which prevents dimerization of the DD, also blocks induction of these activities. MyD88-induced NF-κB activation is inhibited by the dominant negative versions of TRAF6 and IRAK, which also inhibit IL-1-induced NF-κB activation. Overexpression of MyD88-lpr or MyD88-Toll (expressing only the Toll domain) acted to inhibit IL-1-induced NF-κB and JNK activation in a 293 cell line overexpressing the IL-1RI. MyD88 coimmunoprecipitates with the IL-1R signaling complex in an IL-1-dependent manner.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Supported by the Human Frontier Science Program.
↵§§ To whom correspondence should be addressed: Institute of Biochemistry, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland. Tel.: 41 21 692 5738; Fax: 41 21 692 5705; E-mail: jurg.tschopp{at}ib.unil.ch.
↵1 The abbreviations used are: DD, death domain; JNK, Jun N-terminal kinase; IL, interleukin; IL-1R, interleukin 1 receptor; AcP, accessory protein; IRAK, IL-1 receptor-associated kinase; NF, nuclear factor; GST, glutathione S-transferase; TNF, tumor necrosis factor; DTT, dithiothreitol; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophroresis; PCR, polymerase chain reaction; HIV, human immunodeficiency virus; Luc, luciferase; β-gal, β-galactosidase; db, DNA binding.
- Received August 25, 1997.
- Revision received February 19, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.